Epilepsy

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Introduction

cannabinoids have excellent therapeutic potential in epilepsy. In the brain, cannabinoids tend to keep neuronal activity wihtin acceptable boundaries. More importantly, cannabinoids prevent hypersynchronisation of cortical neurons (which is the very definition of a seizure).

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Prescription Advice

Although preclinical data provides evidence for the therapeutic effect of several cannabinoids in epilepsy, only THC and CBD are readily available. Clinical evidence also suggests THC and CBD are therapeutic in epilepsy.

Please note that, while based on preclinical and/or clinical research, this prescription advice is solely intended as a guideline to help physicians determine the right prescription. We intend to continuously update our prescription advice based on patient and/or expert feedback. If you have information that this prescription advice is inaccurate, incomplete or outdated please contact ushere.

cannabinoids reduce the number of neurotransmitter vesicles available for fusion (García-Morales et al., 2015).

So far, the only cannabinoids proven to be effective against epilepsy in clinical trials are CBD and THC (see below), but other cannabinoids like CBDV and THCV are likely to follow. In rats, THC and other synthetic CB1 agonists, reduces synchronous firing of hippocampal principal neurons, suggesting a direct role for THC in seizure prevention (Goonawardena et al., 2011).

Similarly, CB1 activation decreases synchrony in cortical neurons (Sales-Carbonell et al., 2013) suggesting THC (like substances) can be used to suppress seizures. In healthy human volunteers, 10 mg oral THCV reduced functional network connectivity in the brain (measured by fMRI)(Rzepa et al., 2015). Although this does not prove anything in itself, it does support the idea that cannabinoids can reduce network synchronization. In heterologous cells (HEK293), THC and CBD were found to inhibit T-type calcium channels with an IC50 of approximately 1μM (Ross et al., 2008). THC-mediated inhibition was frequency dependent where CBD-mediated inhibition was not.

As T-type calcium channels function in thalamus-mediated synchronization of brain regions and are implicated in various types of epilepsy, THC and CBD are likely to suppress seizure generation. In human neuroblastoma cells (SH-SY5Y) and mouse cortical neurons CBD and CBG both blocked sodium channels Nav1.1, 1.2 and 1.5 (Hill et al., 2014). Interestingly, CBD but not CBG protected against pentyleneterzole (PTZ)-induced seizures in rat, suggesting that the anti-convulsant effect of CBD is not just through blocking sodium channels. Interestingly, cannabis was also shown to prevent the development of seizures/epilepsy (Brust et al., 1992), suggesting a prophylactic effect of cannabinoids. In mice, stimulating CB1 receptors (ACEA) or blocking TRPV1 receptors (capsazepine) protected against PTZ-induced seizures (Naderi et al., 2015). Interestingly, co-administration of both compounds attenuated the anti-convulsive effect, suggesting an interaction between CB1 and TRPV1 mediated signaling. In rats, the synthetic CB1 agonist WIN 55-212-2 was protective against the development of epilepsy when administered after an episode of status epilepticus (induced by pilocarpine)(Di Maio et al., 2014).

Sub-acute treatment with WIN 55-212-2 for 15 days dramatically reduced the frequency of spontaneous seizures, their duration and intensity and the incidence of neuronal oxidative damage. In rats, WIN 55-212-2 delayed the onset of audiogenic epilepsy by two weeks suggesting a preventive effect of Cannabinoid on the development of epilepsy as well as a curative effect (Vinogradova and van Rijn, 2015).

In 1949, the anti-convulsant activity of THC was tested on 5 children with severe grand mal epilepsy. In 3 children, THC was equally effective as previously tried therapies, in one child seizures were almost completely prevented and in the last one all seizures were stopped (Davis and Ramsey, 1949).

In one patient with idiopathic generalized epilepsy the effect of smoked cannabis sativa and cannabis indica was tested using EEG recordings. The results indicate that cannabis use reduces both interictal and ictal events warranting larger scale trials (Sivakumar et al., 2017).

Two clinical trials in the 1980’s investigated the therapeutic properties of CBD in epilepsy. CBD was found to be effective in 50% of patients, meaning that seizure occurrence was reduced by >50%. The occurrence of seizures was reduced by less than 50% in a further 37.5% with no effect observed in the remaining 12.5% (Cunha et al., 1980; Pickering et al., 2011).

Apart from seizure reduction, CBD was reported to significantly improve Quality Of Life in children with epilepsy (Rosenberg et al., 2017).

In one very public case, a girl with Dravet syndrome (loss of function mutation in the sodium channel SCN1A), went from having more than 50 convulsive seizures per day to less than 3 nocturnal seizures per month by using extract from a Cannabis variety Charlotte’s Web, which has a THC content of 0.5% and a CBD content of 17% (Maa and Figi, 2014). The authors stress that there is synergy between cannabinoids and that cannabis extracts are superior to individually purified cannabinoids.

A meta-analysis of studies investigating the effect of CBD in treatment-resistant epilepsy found that 20 mg/kg CBD was more effective than placebo in reducing seizure frequency by more than 50%. Pooled data suggests that 55.8% report improved quality of life, 48.5% of patients experience >50% reduction of seizures and 8.5% experience complete seizure freedom (Stockings et al., 2018).

CBD was tested in five patients with Sturge-Weber syndrome with treatment-resistant epilepsy. After 8 weeks of CBD, two out of five patients reported a >50% seizure reduction and improved quality of life, suggesting a positive effect of CBD treatment (Kaplan et al., 2017).

Other cannabinoids (such as CBDV or THCV) are likely to have therapeutic effects as well but this has not yet been investigated.

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